1-phenoxy-2-hydroxy-3-isopropylamino-propanes and salts thereof

ABSTRACT

1-SUBSTITUTED PHENOXY-2-HYDROXY-3-N-ISOPROPYL-AMINOPROPANES AND ACID ADDITION SALTS THEREOF, POSSESSING BRADYCARDIA ACTIVITY AND N-ISOPROPYL-NOR-ADRENALINE ANTAGONISTIC ACTIVITY.

United States Patent Off ce 3,537,852 Patented Jan. 25, 1972 U.S. Cl.260--570.7 3 Claims ABSTRACT OF THE DISCLOSURE l-substitutedphenoxy-2-hydroxy-3-N-isopropyl-aminopropanes and acid addition saltsthereof, possessing bradycardia activity and N-isopropyl-nor-adrenalineantagonistic activity.

The present application is a continuation-in-part application ofcopending, commonly assigned, application Ser. No. 391,012, filed Aug.20, 1964, now abandoned.

This invention relates to novel 1-aryloXy-2-hydroXy-3-isopropylamino-propanes and acid addition salts thereof, as well as tovarious methods of preparing these compounds.

More particularly, the present invention relates to 1- substitutedphenoxy-Z-hydroxy-3-isopropylamino-propanes of the formula wherein R isselected from the group consisting of chlorine, straight or branchedalkyl of 1 to 4 carbon atoms, straight or branched alkoxy of 1 to 4carbon atoms, hydroxy, hydroxyalkyl of 1 to 4 carbon atoms, hydroxycarbonyl, alkoxycarbonyl of l to 4 carbon atoms, alkanoyl of 2 to 4carbon atoms and aralkoxy, and x is a whole number from 1 to 3,inclusive, provided, however, that R is other than o-chloro, o-methyland o-methoxy when x is 1 and other than 2,6-dimethyl and 2,4-dimethylwhen x is 2, and their non-toxic, pharmacologically acceptable acidaddition salts.

The compounds according to the present invention may be prepared by anumber of different methods involving known chemical reactionprinciples; however, among these, the following methods have been foundto be most convenient and efficient:

METHOD A By reacting an epoxide of the formula where R and x have thesame meanings as in Formula I, with isopropylamine in the presence of aninert solvent, such as ethanol.

METHOD B By reacting a l-substituted phenoxy-2-hydroXy-3-hal0 propane ofthe formula 0H (III) wherein R and x halve the same meanings as inFormula I and Hal is halogen, with isopropylamine in the presence of aninert solvent, such as ethanol.

METHOD C By reacting a l-substituted phenoxy-Z-hydroxy-B- amino-propaneof the formula O-CH CIE[-OH NH H wherein R and x have the same meaningsas in Formula I, with an isopropyl halide.

METHOD D By hydrolizing and oxazolidone of the formula @o-cm-zn-om (RN-CI-I(CH3)2 1 d v wherein R and x have the same meanings as in FormulaI.

METHOD B By reacting a substituted phenolate of the formula (R)x whereinR and x have the same meanings as in Formula I and M is a monovalentcation, preferably an alkali metal, with a l halo 2 hydroxy 3isopropylaminopropane.

METHOD F By hydrogenating a l-substituted phenoxy-2-hydroxy-3-benzylisopropylamino-propane of the formula wherein R and x have thesame meanings as in Formula I, with catalytically activated hydrogen ora boranate, such as aluminum boranate.

The starting compounds of the Formulas H to VIII for the above methodsare known compounds or may readily be prepared by known methods.

The free bases of the Formula I obtained by any of the above methods, Athrough G, may subsequently be transformed into non-toxic,pharmacologically acceptable acid addition salts by conventionalmethods, that is, by acidifying a solution of the free base with thedesired acid and recovering the acid addition salt by evaporation of thesolvent or by precipitation, for instance.

Examples of non-toxic, pharmacologically acceptable acid addition saltsof the bases are those formed with hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methane sulfonic acid, acetic acid,lactic acid, tartaric acid, ascorbic acid, 8-chlorotheophylline and thelike.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood,

however, that our invention is not limited to the specific examplesgiven below.

EXAMPLE 1 Preparation of 1-(2,4'-dichlorophenoxy) 2 -hydroxy-3-isopropylamino-propane and its hydrochloride by Method A A solution of100 gm. (1.7 mols) of isopropylamine in 60 cc. of water was stirred intoa solution of 94.5 gm. (0.405 mol) ofl-(2,4-dichlorophenoxy)-propyleneoxide. After the exothermic reactionhad subsided, the reaction mixture was heated for two hours at 60 C.Thereafter, the aqueous ethanol was distilled off, and the solid residuewas dissolved in aqueous hydrochloric acid comprising more than thetheoretical stoichiometric molar equivalent of hydrochloric acid. Theaqueous acid solution was extracted with ether and was then madealkaline with sodium hydroxide, whereby a solid crystalline precipitatewas formed which was filtered off and dried over phosphorus pentoxide.112.5 gm. (93.7% of theory) of 1-(2,4'-dichlorophenoxy) 2 hydroxy 3isopropylamino-propane of the formula were obtained. The product wasdissolved in ethanol, the resulting solution was acidified with etherealhydrochloric acid, and the precipitate formed thereby was recrystallizedfrom a mixture of ethanol and ether. The hydrochloride of the base thusobtained had a melting point of 150.5l52 C.

EXAMPLE 2 Preparation of1-(3-methyl-phenoxy)-2-hydroxy-3-isopropylamine-propane and itshydrochloride by Method A A solution of 59 gm. (1 mol) of isopropylaminein 60 cc. of water was added to a solution of 82 gm. (0.5 mol) ofl-(3'methyl-phenoxy)-propyleneoxide in 400 cc. of ethanol. After theexothermic reaction had subsided, the reaction mixture was stirred fortwo hours at 60 C. Thereafter, the volatile components of the reactionmixture were distilled off and the solid residue was dissolved inaqueous hydrochloric acid. The acid solution was ex tracted with etherand was then made alkaline with sodium hydroxide. The precipitate formedthereby was separated and dried over phosphorus pentoxide, yielding101.9 gm. (91.3% of theory) of raw l-(3'-methyl-phenoxy)-2-hydroxy-3-isopropylamino-propane of the formula CH3 oongpu-ornun-on 011mAfter recrystallization from a mixture of ethyl acetate and petroleumether the base had a melting point of 7576 C.

The base was dissolved in ethanol, the resulting solution was acidifiedwith ethereal hydrochloric acid, and the precipitate was recrystallizedfrom a mixture of ethanol and ether. The hydrochloride of the base thusobtained had a melting point of 12012l C.

EXAMPLE 3 Preparation of 1-(2',3-dimethyl-phenoxy)-2-hydroxy-3-isopropylamino-propane and its hydrochloride by Method A 17.8 gm. (0.1mol) of l-(2',3-dimethyl-phenoxy)-propyleneoxide were dissolved in 100cc. of ethanol, the resulting solution was admixed with a solution of17.7 gm. (0.3 mol) of isopropylamine in 15 cc. of water, and the mixturewas first allowed to stand at room temperature for two hours and wasthen heated for three hours at 5050 C. Thereafter, the aqueous ethanolwas distilled off, the residue was dissolved in hydrochloric acid, and

the solution was extracted with ether. The aqueous phase was madealkaline with aqueous 20% sodium hydroxide, whereby a crystallineprecipitate was formed which was separated and dried. 21.5 gm. (90.7% oftheory) of 1-(2', 3'-dimethyl-phenoxy)-2-hydroxy 3isopropylamino-propane of the formula were obtained.

The base was dissolved in ethanol, the solution was acidified withethereal hydrochloric acid, and the precipitate formed thereby wasrecrystallized from a mixture of ethanol and ether. The hydrochloride ofthe base thus obtained had a melting point of l50l5l C.

EXAMPLE 4 Preparation of1-(3-chloro-phenoxy)-2-hydroxy-3-isopropylamine-propane and itshydrochloride by Method A 14.8 gm. (0.08 mol) ofl-(3-chl0ro-phenoxy)-propyleneoxide in ethanolic solution were reactedwith isopropylamine as described in the preceding examples. Afterevaporating the ethanol, the precipitate,1-(3'-chlorophenoxy)-2-hydroxy-3-isopropylamino-propane, was separatedby vacuum filtration, dried and dissolved in a small amount of ethanoland the resulting solution was acidified with ethereal hydrochloricacid. The crystalline precipitate formed thereby was separated andrecrystallized from a mixture of ethanol and ether. 12.6 gm. (56% oftheory) of the hydrochloride of the formula were obtained. The producthad a melting point of 86- 88 C.

EXAMPLE 5 Preparation of 1-(2',4,5-trichloro-phenoxy)-2-hydroxy-3-isopropylamino-propane and its hydrochloride by Method B 0.1 mole of1-(2,4,5'-trichlorophenoxy)-3-bromopropanol-Z was dissolved in 75 cc. ofethanol and 0.3 mole of isopropylamine were added to the solution. Afterthe exothermic reaction had subsided, the reaction mixture was allowedto stand overnight at room temperature after which it was heated to 60C. for three hours. The ethanol was distilled off in vacuo and theresidue was worked up as described in Example I to obtain the free base,1 (2,4',5' trichloro phenoxy) 2 hydroxy- 3-isopropylamino-propane. Thefree base then converted into its hydrochloride which had a meltingpoint of 156- 158 C. after recrystallization from a mixture of ethanoland ether.

EXAMPLE 6 Preparation of l-(3'-hydroXy-phenoxy)-2-hydroxy-3-isopropylamino-propane and its hydrochloride 11.2 gm. (0.05 mol) of1-(3-amino-phenoxy)-2-hydroxy-3-isopropylamino-propane were dissolved ina cold mixture of 50 cc. of water and 10 cc. of concentrated sulfuricacid. To the resulting solution, 6.9 gm. (0.1 mol) of NaNO in 30 cc. ofwater were added dropwise, and the solution was allowed to stand at roomtemperature for 12 hours. Thereafter the solution was made alkaline withammonia and was then extracted with ether. The ether layer was driedover MgSO and the ether distilled off, and the solid residue wascrystallized from ethyl acetate. The base thus obtained was dissolved inacetonitrilc, the resulting solution was acidified with etherealhydrochloric acid, and the precipitate formed thereby was recrystallizedfrom a mixture of ethanol and ether. The 1 (3 hydroxyphenoxy)-2-hydroxy-3-isopropylamino-propane hydrochloride thus obtainedhad a melting point of 125-127 C.

EXAMPLE 7 Using a procedure analogous to that described in Example 1, 1(4' methoxy phenoxy)-2-hydroxy-3- isopropylamino-propane was preparedfrom 4-methoxyphenoxy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 141-142 C.

EXAMPLE 8 Using a procedure analogous to that described in Example 1,1-(4'-methyl phenoxy) 2 hydroxy-3- isopropylamino-propane was preparedfrom 4-methy1- phenoxy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 141-142 C.

EXAMPLE 9 Using a procedure analogous to that described in Example 1, 13,4 dichloro phenoxy) 2 hydroxy 3-isopropylamino-propane was preparedfrom 3,4-dichlorophenoxy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 151-152" C.

EXAMPLE 10 Using a procedure analogous to that described in Example 5, 1(3',4'-dimethyl phenoxy)-2-hydroXy-3- isopropylamino-propane wasprepared from 1-(3,4-dimethylphenoxy)-3-chloro isopropanol andisopropylamine. Its hydrochloride had a melting point of 148- 149 C.

EXAMPLE 11 Using a procedure analogous to that described in Example 5, 1(2,5'-dimethyl phenoxy)-2-hydroxy-3- isopropylamino-propane was preparedfrom 1-(2,5-dimethylphenoxy 3 chloro-isopropanol and isopropylamine. Itshydrochloride had a melting point of 123- 125 C.

EXAMPLE 13 Using a procedure analogous to that described in Example 1, 1(4 chloro phenoxy) 2 hydroxy 3- isopropylamino-propane was prepared from4-chlorophenoxy-propyleneoxide and isopropylamine. Its hydro chloridehad a melting point of 152154 C.

EXAMPLE 14 Using a procedure analogous to that described in Example 1, 1(4-hydroxy-phenoxy) 2 hydroxy-3- isopropyla-mino-propane of the formulaHo-Q-O-Cm-pH-oIn-Nn-omornn was prepared from 4-hydroxyphenoxypropyleneoxide and isopropylamine. Its hydrochloride had a melting pointof 166-169 C.

EXAMPLE 15 Using a procedure analogous to that described in Example 1,1-(2',5'-dichloro phenoxy) 2 hydroxy-3- isopropylamino-propane wasprepared from 2,5-dichlo1ophenoxy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 153-154" C.

6 EXAMPLE 16 Using a procedure analogous to that described in Example 1,1 (3-methoxy phenoxy) 2 hydroxy-3- isopropylamino-propane was preparedfrom 3-methoxyphenoxy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 77-78.5 C.

EXAMPLE 17 Using a procedure analogous to that described in Example 5, 1(2'-tert.butyl 4 methyl phenoxy)-2- hydroxy-3-isopropylamino-propane ofthe formula IX W was prepared from 1-(2'-tert.butyl-4-methylphenoxy)-3-chloro-isopropanol and isopropylamine. Its hydrochloride had a meltingpoint of 161-162 C.

EXAMPLE 18 Using a procedure analogous to that described in Example 1,1-(2-hydroxy-phenoxy)-2-hydroxy-3-isopropylamino-propane was preparedfrom 2-hydroxyphenoxypropyleneoxide and isopropylamine. Itshydrochloride had a melting point of 126-128 C.

EXAMPLE 19 Using a procedure analogous to that described in Example 5,1-(2 methyl 4' tert.butyl-phenoxy)-2-hydroxy-3-isopropylamino-propanewas prepared from 1-(2'- methyl 4tert.butyl-phenoxy)-3-chloro-isopropanol and isopropylamine. Itshydrochloride had a melting point of 1 10-1 15 C.

EXAMPLE 20 Using a procedure analogous to that described in Example 1,1-(2',6'-dichloro-phenoxy)-2-hydroxy-3-isopropylamino-propane wasprepared from 2,6-dichlorophenoXy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 130-131 C.

EXAMPLE 21 Using a procedure analogous to that described in Example 1,1-(2',3-dichloro-phenoxy)-2-hydroxy-3-isopropylamino-propane wasprepared from 2,3-dichlorophenoxy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 144-146" C.

EXAMPLE 22 Using a procedure analogous to that described in Example 1,1-(4 -benzyloxy-phenoxy)-2-hydroxy-3-isopropylarnine-propane of theformula can-orn-o-Qo-onz-prr-oln-Nn-omoln)2 was prepared from4-benzyloxyphenoxypropyleneoxide and isopropylamine. Its hydrochloridehad a melting point of -166 C.

- EXAMPLE 23 Using a procedure analogous to that described in Example 1,1-(2',3,5-trimethyl-phenoxy)-2-hydroxy-3- isopropylamino-propane wasprepared from 2,3,5-trimethylphenoxy-propyleneoxide and isopropylamine.Its hydrochloride had a melting point of 158-160" C.

EXAMPLE 24 Using a procedure analogous to that described in Example 1,1(3-methyl-5'-ethyl-phenoxy)-2-hydroxy-3- isopropylamino-propane wasprepared from 3-methyl-5- ethyl-phenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 105-107 C.

7 EXAMPLE 25 Using a procedure analogous to that described in Example 1,1-(4'-propionyl-phenoxy)-2-hydroxy-3-1sopropylamino-propane of theformula was prepared from 4-propionylphenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 168-170 C.

EXAMPLE 26 Using a procedure analogous to that described in Example 1,1-(3',5-dichloro-phenoxy)-2-hydroxy-3-isopropylamino-propane wasprepared from 3,5-dichlorophenoxy-propyleneoxide and isopropylamine. Itshydrochloride had a melting point of 142-144" C.

EXAMPLE 27 Using a procedure analogous to that described in Example 1,1-(3,4',5 trimethyl phenoxy)-2-hydroxy-3- isopropylamino-propane wasprepared from 3,4,5-trimethylphenoxy-propyleneoxide and isopropylamine.Its hydrochloride had a melting point of 174-l76 C.

EXAMPLE 28 Using a procedure analogous to that described in Example 1,1-(2,4,6 trimethyl phenoxy)-2-hydroxy-3- isopropylamine-propane wasprepared from 2,4,6-trimethyl-phenoxy-propyleneoxide and isopropylamine.Its hydrochloride had a melting point of 167-168 C.

EXAMPLE 29 Using a procedure analogous to that described in Example 1,1-(2',4,5' trimethyl phenoxy)-2-hydroxy-3- isopropylamino-propane wasprepared from 2,4,5-trimethylphenoxy-propyleneoxide and isopropylamine.Its hydrochloride had a melting point of 167-168 C.

EXAMPLE 30 Using a procedure analogous to that described in Example 1,1-(2'-methyl-6-chloro-phenoxy)-2-l1ydroxy-3- isopropylamine-propane ofthe formula Q-o-om-on-cm-mr-cn 0H3);

was prepared from 2-methyl-6-chlorophenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 126-128 C.

EXAMPLE 3 1 Using a procedure analogous to that described in Example 1,1-(2'-methyl-4'chloro-phenoxy)-2-hydroxy-3- isopropylamino-propane wasprepared from 2-methyl-4- chlorophenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 144-146 C.

EXAMPLE 32 Using a procedure analogous to that described in Example 1,1-(2'-propionyl-4-chloro-phenoxy)-2-hydroxy- 3-isopropylamino-propanewas prepared from Z-propionyl 4 chlorophenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 120- 123 C.

EXAMPLE 33 Using a procedure analogous to that described in Example 1, 1(3,5' dimethyl-4'-chloro-phenoxy)-2-hydroxy-3-isopropylamino-propane wasprepared from 3,5- dimethyl-4-chlorophenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 165- 8 EXAMPLE34 Using a procedure analogous to that described in Example 1, 1(3-methyl-4'-chl0ro-phenoxy)-2-hydroxy-3- isopropylamino-propane wasprepared from 3-methyl-4- chlorophenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 139141 C.

EXAMPLE 35 Using a procedure analogous to that described in Example 1,1-(2-propionyl-5-methyl-phenoxy)-2-hydroxy- 3-isopropylamino-propane wasprepared from 2-pr0pionyl 5 methylphenoxy-propyleneoxide andisopropylamine. Its hydrochloride had a melting point of 136- 138 C.

EXAMPLE 36 Using a procedure analogous to that described in Example 1, 1(2-ethyl-phenoxy)-2-hydroxy-3-isopropylamino-propane M.P. -775 C., wasprepared from 2- ethyl-phenoxy-propyleneoxide and isopropylamine.

EXAMPLE 37 Preparation of 1- 3-hydroxymethylphenoxy)-2-hydroxy-3-isopropylamino-propane -HCl 23.4 gm. (0.13 mole) of1-(3-hydroxymethylphenoxy)- 2,3 epoxy-propane were reacted with 23.4 gm.(0.04 mole) of isopropylamine using the procedure of Example 1 to obtain1-(3-hydroxymethylphenoxy)-2-hydroxy- 3-isopropylamino-propane having amelting point of 79- C. The corresponding hydrochloride, precipitatedfrom ethanol with ethereal HCl, had a melting point of 98101 C.

EXAMPLE 38 Preparation of1-(3-methoxycarbonylphenoxy)-2-hydroxy-3-isopropylamino-propane -HCl20.8 gm. (0.1 mole) of 1-(3 methoxycarbonylphenoxy)-2,3 epoxy-propanewas reacted with isopropylamine accordiug to the procedure of Example 1to obtain 1-(3 methoxycarbonyl-phenoxy) 2hydroxy-B-isopropylamino-propane having a melting point of 7576 C. Itshydrochloride had a melting point of 117-119 C.

EXAMPLE 39 Preparation of 1- 3-hydroxycarbonylphenoxy -2-hydroxy-3-isopropylamino-propane HCl EXAMPLE 40 Preparation of 1-2-methoxycarbonylphenoxy -2- hydroxy-3-isopropylamino-propane-HCl Usingthe procedure of Example 1, 35.2 gm. (0.17 mole.) of1-(2-methoxycarbonylphenoxy) 2,3-epoxypropane were reacted withisopropylamine to obtain 31 gm. of1-(Z-methoxycarbonylphenoxy)-2-hydroxy-3-isopropylamino-propane having amelting point of 93-95 C. Its hydrochloride had a melting point of 78-81C.

EXAMPLE 41 Preparation of 1-(4-methoxycarbonylphenoxy)-2-hydroxy-3-isopropylamino-pro pane HCl Using the procedure of Example 1,107 gm. (0.515 mole) of 1-(4 methoxycarbonylphenoxy) 2,3-epoxypropanewere reacted with isopropylamine to obtain 67.8 gm. ofl-(4-methoxycarbonylphenoxy)-2-hydroxy- 3-isopropylamino-propane havinga melting point of 85- 87 C. after recrystallization from ethyl acetate.Its hydrochloride had a melting point of 171-172" C.

EXAMPLE 42 Preparation of 1-(2-hydroxycarbonyl-4-chlorophenoxy)-Z-hydroxy-3-isopropylamino-propane Using the procedure of Example 39,1-(2-methoxycarbonyl-4-chlorophenoxy)-2 hydroxy 3 isopropylamino-propanewas treated with sodium hydroxide to obtain 1-'(2-'hydroxycarbonyl 4chlorophenoxy)-2-hydroxy-3-isopropylamino-propane. Its hydrochloride hada melting point of 181-183 C.

The compounds according to the present invention, that is, thoseembraced by Formula I, and their nontoxic, pharmacologically acceptableacid addition salts, have useful pharmocodynamic properties. Moreparticularly, they produce bradycardia and at the same time act asN-isopropylnoradrenaline (Isoproterenol) antagonists. Thus, thetachycardiac effects caused by the administration ofN-isopropylnoradrenaline are suppressed or eliminated by prioradministration of one of the compounds of the present invention, andcardiac arrhythmia are equalized by them. In other words, the compoundsaccording to the present invention block the sympathetic nervous systemof the heart, which has heretofore not been possible withchemotherapeutic agents. Consequently, the areas of indication for thecompounds of the present invention are hypertension, angina pectoris,cardiac arrhythmia, digitalis intoxication and pheochromocytomadisorders.

The compounds of Formula I in which R is alkoxy, preferably methoxy, andalkyl having more than one carbon atom have a high bradycardia activity.For example, 1 (3' methoxy-phenoxy) 2 hydroxy 3 isopropylamino-propanehas a bradycardia activity of 24 as compared to the known compound, 1(2' methoxyphenoxy) 2 hydroxy 3 isopropylamino propane (J.A.C.S., vol82/s, p. 1169), which in the same test has a bradycardia activity of0.5.

The other compounds of Formula I, especially those in which R is methyl,are particularly valuable as isoproterenol antagonists. For example, 1(3 methylphenoxy) 2 hydroxy 3 isopropylamino propane is 5 times moreeffective as an isoproterenol antagonist than the known compound,dichloroisoproterenol, and is useful for the treatment of originalcardiac activities such as angina pectoris and smooth out cardiacarrhythmia.

In View of the presence of an asymmetric carbon atom in the 2-positionof the propylene chain, the compounds of the present invention exist notonly in the form of racemic mixtures but also in the form of opticalantipodes. The optical antipodes may be separated from the racemates byconventional methods and have the same pharmocodynarnic properties asthe racemates.

For therapeutic purposes in animals, the compounds of the presentinvention are administered perorally or parenterally as activeingredients in conventional dosage unit compositions, that is,compositions in dosage unit form consisting essentially of a majoramount of an inert pharmaceutical carrier and one dosage unit of theactive ingredient. Dosages of the compounds pursuant to the presentinvention is from 0.01 to 5 mgm/kg, depending upon the route ofadministration and the intensity of the effect desired or required.Thus, for oral administration the dosage range is 0.45 mgm./kg.,preferably 1-3 mgm./kg.; for intravenous administration it is 0.01-02.mgm./kg., preferable 0.020.1 mgm./kg.; and for subcutaneousadministration it is 0.020.1 mgm./kg., preferably 0.1-0.3 mgm./ kg.Typical examples of dosage com- 10 positions are tablets, coated pills,suspensions, solutions, suppositories and the like.

The following examples illustrate a few dosage unit compositionscomprising a compound according to the present invention as an activeingredient. The parts are parts by weight unless otherwise specified.

EXAMPLE 43 Hypodermic solution The solution is compounded from thefollowing ingredients:

Parts 1-(3' methyl phenoxy) 2 hydroxy-3-isopropylamino-propanehydrochloride 10.0 Sodium chloride 5.5

Double distilled water q.s.ad 1000.0 parts by vol.

Compounding procedure The isopropanol derivative and sodium chloride arefirst dissolved in about one-half of the required amount of water, thesolution is then diluted with the remaining amount of distilled water tothe desired volume, and the finished solution is filtered until freefrom suspended particles. Thereafter, it is filled into 2 cc.-ampules,which are sterilized and then sealed. Each ampule contains 10 mgm of theactive ingredient.

EXAMPLE 44 Tablets The tablet composition is compounded from thefollowing ingredients:

Parts 1-(3 methyl-phenoxy) 2 hydroxy-3-isopr0pyl amino-propanehydrochloride 25.0 Calcium phosphate 189.0 Corn starch 194.0- Colloidalsilicic acid 14.0 Polyvinylpyrrolidone 6.0 Soluble starch 10.0 Magnesiumstearate 2.0

Compounding procedure The individual ingredients are thoroughly admixedwith each other, and the intimate mixture is pressed in conventionalfashion into 440 mgm. tablets. Each tablet contains 25 mgm. of theactive ingredient. 7

Although the above illustrative dosage unit compositions comprise onlyone of the compounds of the present invention as an active ingredient,it should be understood that any of the other compounds embraced byFormula I or a non-toxic acid addition salt thereof, either in theracemic or in the optically active dor l-form, may 'be substitutedtherefor in Examples 43 and 44. Moreover, the amounts of the activeingredient in the illustrative examples may be varied within theindicated limits to meet particular requirements, as may the amounts andnature of the inert ingredients.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to those particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A compound selected from the group consisting of racemic 1 phenoxy 2hydroxy 3 isopropylaminopropane compounds of the formula 2. A compoundof claim 1 which is 1-(3 hydroxy- 10 methyl-phenoxy) -2-hydroxy-3-isopropylamino-pr0pane.

3. A compound of claim 1 which 1-(4' benzyloxyphenoxy)-2-hydroxy-3-isopropylamino-propane.

References Cited UNITED STATES PATENTS 3,275,654 9/1966 Wilhelm et a1.260570.7 X 3,432,545 3/1969 Howe 260--50l.17 3,501,769 3/1970 CroWtheret a1. 260570.7 X

ROBERT V. HINES, Primary Examiner US. Cl. X.R.

260-253, 307 C, 343.7, 348 R, 47 R, 501.17, 501.19, 519, 570.6, 612 I;424330

